Mechanistic Networks, Cellular Specificity, and Therapeutic Opportunities of Ferroptosis in Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by epithelial barrier disruption, oxidative stress, immune dysregulation, and defective mucosal healing. Recent studies have identified ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, as a key mechanism linking these processes. This review summarizes the current progress in understanding the role of ferroptosis in colitis. Available evidence shows that ferroptosis occurs in both human UC and experimental colitis models, with intestinal epithelial cells representing the best-established target compartment. Recent studies have further expanded this concept to reparative immune cells, particularly type 2 (M2) macrophages, thereby indicating that ferroptosis contributes not only to barrier injury but also to impaired mucosal healing. Mechanistically, colitis-associated ferroptosis is governed by interconnected networks involving solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) failure, acyl-CoA synthetase long chain family member 4 (ACSL4)-dependent lipid remodeling, iron overload, mitochondrial reactive oxygen species (ROS) amplification, inflammatory signaling, and N6-methyladenosine (m6A)-mediated post-transcriptional regulation. In parallel, microbiota-derived metabolites and dietary factors can either suppress or exacerbate ferroptotic injury. Therapeutically, ferroptosis-targeted strategies, including iron chelation, nutrient-based interventions, natural products, exosomes, and nanoplatforms show promising preclinical efficacy. Overall, ferroptosis provides a connected framework for understanding colitis pathogenesis and provides new opportunities for biomarker development and mechanism-based therapies.